THC Derivatives
Δ9-Tetrahydrocannabinol [THC], depicted below as Formula I under alternate numbering systems, is the major psychoactive constituent of marijuana.
In addition to mood-altering effects, THC has been reported to exhibit other activities, some of which may have therapeutic value. The potential therapeutic value of THC has led to a search for related compounds which, while devoid of psychoactive effects, retain the activities of potential medicinal value.
Previous work with Δ8-tetrahydrocannabinol [6aR,7,10,10aR-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, hereinafter referred to as Δ8-THC], which is depicted below in Formula II, has indicated that certain derivatives of this compound may prove clinically useful.
The 11-carboxy derivative of Δ8-THC [Δ8-THC-11-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (See U.S. Pat. No. 4,973,603, incorporated herein by reference.) Another derivative, (3S,4S)-11-hydroxy-Δ8-THC-1′,1′dimethylheptyl, essentially free of the (3R,4R) form, has been reported to possess analgesic and anti-emetic activities. (See U.S. Pat. No. 4,876,276, also incorporated herein by reference.)Interstitial Cystitis
Interstitial cystitis (IC) is a chronic pelvic pain disorder that results in recurring discomfort or pain in the bladder and the surrounding pelvic region. The symptoms of IC vary form case to case and even in the same individual. Patients may experience mild discomfort, pressure, tenderness, or intense pain in the bladder and pelvic area. Symptoms may include an urgent need to urinate and/or frequent need to urinate. The pain may change in intensity as the bladder fills with urine or as it empties.
In IC, the bladder wall may be irritated and become scarred or stiff. Glomerulations (pinpoint bleeding caused by recurrent irritation) may appear on the bladder wall. Some people with IC find that their bladders cannot hold much urine, which increases the frequency of urination. Also, people with IC often experience pain during sexual intercourse.
Because IC symptoms and severity vary greatly, most researchers believe that it encompasses not one, but several, diseases. In the past, cases were mainly categorized as ulcerative IC or nonulcerative IC, based on whether ulcers had formed on the bladder wall. Even today, it is easier to define IC by what it isn't than by what it is, and to reach a diagnosis of IC, the physician must first rule out bacterial cystitis—the most common urinary tract infection—whose symptoms it most closely resembles. Bladder cancer, kidney stones, vaginitis, endometriosis, sexually transmitted diseases, tuberculosis, and radiation cystitis, as well as prostate infections in men, are some other conditions that must be considered. Thus, IC is a diagnosis of exclusion.
Although some of the symptoms of IC resemble those of a bacterial infection, medical tests reveal no organisms in the urine of patients with IC. Furthermore, patients with IC do not respond to antibiotic therapy. Researchers are still working to understand the causes of IC and to find effective treatments. Some have suggested it may be an autoimmune disorder of the bladder's connective tissue, in which the body's defense mechanisms against invading bacteria turn suddenly against healthy tissue. In some patients, special white blood cells called mast cells, which are associated with inflammation, are found within the bladder's mucous lining. It has also been theorized that the disorder may be an allergic reaction, because many patients have a history of allergies. Some scientists have suggested that certain substances in urine may be irritating to people with IC, but no substance unique to people with IC has as yet been isolated.
Another theory is that a bacterium may be present in bladder cells but not detectable through routine urine tests. Researchers are also beginning to explore the possibility that heredity may play a part in some forms of IC, but no gene has yet been implicated. One theory holds that the inner lining of the bladder (the glycosaminoglycan or GAG layer) that protects the bladder wall from toxic effects of urine may be “leaky,” allowing substances in the urine to penetrate the bladder wall and trigger IC symptoms. A recent study found that 70 percent of IC patients they examined had a “leaky” bladder lining.
There is no cure for IC, and current therapies are aimed at trying to relieve the symptoms, which vary from person to person. People may have flare-ups and remissions, and different patients respond to different treatments. A particular type of therapy may work for a while and then lose its effectiveness. Sometimes, stress or a change of diet triggers symptoms. Occasionally, IC goes into remission spontaneously. Even when symptoms disappear, they may return after days, weeks, months, or years.
Factors that influence the treatment options available typically include whether bladder capacity under anesthesia is great or small, and whether mast cells are present in the tissue of the bladder wall, which may be a sign of an allergic or autoimmune reaction. In some cases, the success or failure of a treatment helps characterize the type of IC. Some current treatments for IC include bladder distention, administration of pharmaceutical compositions by bladder instillation (also known as intravesicular instillation (IVI)), oral administration of pharmaceutical compositions, and transcutaneous electrical nerve stimulation. These treatment options will be described in greater detail below.
Bladder distention is often performed to diagnose IC, but because many patients have noted an improvement in symptoms after the procedure, it is often thought of as one of the first treatment attempts. Researchers are not sure why distention helps, but some believe that it may increase capacity and interfere with pain signals transmitted by nerves in the bladder. Symptoms may temporarily worsen 24 to 48 hours after distention, but should return to predistention levels or improve after 2 to 4 weeks.
During bladder instillation or intravesicular instillation (IVI), which may also be called a bladder wash or bath, the bladder is filled with a solution that is held for varying periods of time, averaging 10 to 15 minutes, before being emptied. IVI is typically performed using dimethyl sulfoxide (DMSO, RIMSO-50). DMSO IVI treatment involves guiding a catheter up the urethra into the bladder. A measured amount of DMSO is passed through the catheter into the bladder, where it is retained for about 15 minutes before being expelled. Treatments are usually given every week or two for 6 to 8 weeks and repeated as needed. Doctors think IVI administration of DMSO works in several ways. Because it passes into the bladder wall, it may reach tissue more effectively to reduce inflammation and block pain. It may also prevent muscle contractions that cause pain, frequency, and urgency.
Pentosan polysulfate sodium (Elmiron®) was the first oral drug developed for IC to have been approved by the FDA. In clinical trials, the drug improved symptoms, but its method of action is unknown. One theory is that it may repair defects that might have developed in the lining of the bladder. The FDA-recommended oral dosage of Elmiron is 100 mg, three times a day. Patients may not feel relief from IC pain for the first 2 to 4 months. A decrease in urinary frequency may take up to 6 months to achieve.
Other oral medications such as aspirin and ibuprofen may be used as a first line of defense against mild discomfort. Doctors may recommend other drugs to relieve pain. Some patients may experience improvement in their urinary symptoms by taking antidepressants or antihistamines. Antidepressants help reduce pain and may also help patients deal with the psychological stress that accompanies living with chronic pain. In patients with severe pain, narcotic analgesics such as acetaminophen with codeine or longer acting narcotics may be necessary.
Transcutaneous electrical nerve stimulation (TENS) involves having mild electric pulses enter the body for minutes to hours two or more times a day, either through wires placed on the lower back or just above the pubic area, between the navel and the pubic hair, or through special devices inserted into the vagina in women or into the rectum in men. Although scientists do not know exactly how TENS relieves IC pain, it has been suggested that the electrical pulses may increase blood flow to the bladder, strengthen pelvic muscles that help control the bladder, or trigger the release of substances that block pain.
None of the currently used treatments for IC is capable of fully relieving the symptoms of IC. Patients frequently combine different treatments in an attempt to address all of their IC symptoms. Further, patients usually cannot achieve long term relief using any of these treatments, and once a particular treatment loses its effectiveness, the patient must introduce a new treatment in its place. Clearly, although numerous treatments have been developed in an attempt to control the symptoms of IC, there is still a great need in the art for effective treatments for IC.